NM_133261.3:c.-77G>A

Variant names:

• chr19-3585521-G-A
• rs34722692
• NM_133261.3:c.-77G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_133261.3(GIPC3):​c.-77G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,070,242 control chromosomes in the GnomAD database, including 6,100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (650 hom., cov: 31)
  • Exomes 𝑓: 0.11 (5450 hom.)
• Consequence: GIPC3 NM_133261.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.77
• Publications: 11 publications found

Genes affected

GIPC3 (HGNC:18183): (GIPC PDZ domain containing family member 3) The protein encoded by this gene belongs to the GIPC family. Studies in mice suggest that this gene is required for postnatal maturation of the hair bundle and long-term survival of hair cells and spiral ganglion in the ear. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2011]

GIPC3 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 15

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 19-3585521-G-A is Benign according to our data. Variant chr19-3585521-G-A is described in ClinVar as Benign. ClinVar VariationId is 1237719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133261.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIPC3	NM_133261.3	MANE Select	c.-77G>A		5_prime_UTR	Exon 1 of 6	NP_573568.1	Q8TF64
	GIPC3	NM_001411144.1		c.-77G>A		5_prime_UTR	Exon 1 of 6	NP_001398073.1	A0A2R8Y651

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIPC3	ENST00000644452.3	MANE Select	c.-77G>A		5_prime_UTR	Exon 1 of 6	ENSP00000493901.2	Q8TF64
	GIPC3	ENST00000644946.1		c.-77G>A		upstream_gene	N/A	ENSP00000495068.1	A0A2R8Y651
	GIPC3	ENST00000854561.1		c.-77G>A		upstream_gene	N/A	ENSP00000524620.1

Frequencies

GnomAD3 genomes AF: 0.0897 AC: 13637 AN: 151978 Hom.: 649 Cov.: 31

Gnomad AFR AF: 0.0821

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0662

Gnomad ASJ AF: 0.0813

Gnomad EAS AF: 0.0518

Gnomad SAS AF: 0.0788

Gnomad FIN AF: 0.0751

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.0856

GnomAD4 exome AF: 0.107 AC: 98501 AN: 918150 Hom.: 5450 Cov.: 19 AF XY: 0.107 AC XY: 46156 AN XY: 430992

African (AFR) AF: 0.0831 AC: 1462 AN: 17596

American (AMR) AF: 0.0653 AC: 249 AN: 3812

Ashkenazi Jewish (ASJ) AF: 0.0712 AC: 554 AN: 7780

East Asian (EAS) AF: 0.0506 AC: 528 AN: 10434

South Asian (SAS) AF: 0.0810 AC: 1446 AN: 17856

European-Finnish (FIN) AF: 0.0742 AC: 753 AN: 10148

Middle Eastern (MID) AF: 0.0721 AC: 149 AN: 2066

European-Non Finnish (NFE) AF: 0.110 AC: 89873 AN: 815874

Other (OTH) AF: 0.107 AC: 3487 AN: 32584

GnomAD4 genome AF: 0.0897 AC: 13642 AN: 152092 Hom.: 650 Cov.: 31 AF XY: 0.0868 AC XY: 6452 AN XY: 74352

African (AFR) AF: 0.0821 AC: 3409 AN: 41522

American (AMR) AF: 0.0662 AC: 1012 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0813 AC: 282 AN: 3470

East Asian (EAS) AF: 0.0518 AC: 267 AN: 5156

South Asian (SAS) AF: 0.0789 AC: 381 AN: 4828

European-Finnish (FIN) AF: 0.0751 AC: 795 AN: 10580

Middle Eastern (MID) AF: 0.0753 AC: 22 AN: 292

European-Non Finnish (NFE) AF: 0.107 AC: 7291 AN: 67936

Other (OTH) AF: 0.0847 AC: 179 AN: 2114

Alfa AF: 0.0239 Hom.: 23

Bravo AF: 0.0885

Asia WGS AF: 0.0770 AC: 265 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	0.98
PhyloP100		1.8
PromoterAI		-0.35	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34722692; hg19: chr19-3585519;